TITLE: Tau oligomer platform validation using lead series candidate in htau mice PROJECT SUMMARY - SBIR Funding Opportunity: Advancing Research on Alzheimer's Disease (AD) and Alzheimer's-Disease-Related Dementias (ADRD) (R43/R44), PAS-17-064 The long-term goal of this program is to develop a disease-modifying, small molecule drug for Alzheimer?s disease (AD) and related tauopathies. There is a critical unmet need for a disease modifying drug for AD. Chronic treatment strategies require economically feasible approaches such as small molecule drugs. This program is progressing to fill this need with a disease modifying drug that, if successful, will have a tremendous impact on the more than five million Americans who currently have AD (projected to be 16 million by 2050) and their caregivers, and will help reduce the current cost of $259 billion (projected to be $1.1 trillion by 2050) to our nation. In the Ph II program the lead compound inhibited tau aggregation in transgenic mice expressing human tau (htau), best representing tau aggregation in AD using a preventive paradigm. This application is for testing the efficacy of the lead in JNPL3 mice that model tau pathology in frontotemporal dementia using both preventive (Aim 1) and therapeutic (Aim 2) treatment strategies. Additionally, the lead will be tested in a therapeutic study in aged htau mice (Aim 3). Analysis of tau pathology (tau aggregation, hyperphosphorylation and misfolding) using ELISAs and immunocytochemistry methods, and behavioral studies for the aged htau and JNPL3 mice will be performed to evaluate how mouse function tracks with reduction of tau pathology. JNPL3 mice develop hind limb paralysis as they age and will be evaluated for latency to fall using a rotarod apparatus. Aged htau mice develop cognitive deficits that will be characterized using the Barnes maze as a measure of spatial learning and memory. For each JNPL3 study there will be three groups of mice (n=20 per group: feed vehicle, 10 mg/kg or 40 mg/kg of compound milled in feed), and for the htau study there will be four groups (n=15 per group: baseline cohort, feed vehicle, 10 mg/kg or 40 mg/kg of compound in feed) to sufficiently power the studies. Compound will be synthesized and formulated into feed prior to starting treatment for each study that will have staggered start times. The length of treatment will be four months for each study that will start at different ages depending on the treatment paradigm and the characteristics of disease progression in the mice models. The in vivo studies, including behavioral characterization and analyses of tau pathology, will be performed independently by Peter Davies, Ph.D., and his laboratory at the Feinstein Institute for Medical Research (Manhasset, NY). Researchers will be blinded to treatment groups during treatment and for behavioral and biochemical analyses. Oligomerix will manage the project, perform additional analyses of mouse specimens with commercially available Abs for tau in parallel with its novel biomarker Abs for tau fragments, and will analyze and report all data. The primary endpoint for each study will be the reduction of insoluble tau with statistical significance; the secondary endpoints for the studies will be dose-dependent reduction of insoluble tau, reduction of phosphorylated tau, and reduction of cleaved tau, and amelioration of motor or cognitive deficits in aged JNPL3 and htau mice, respectively.